Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. We are investigating the induction of apoptosis by activation of death receptors for the ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in breast and ovarian cancer cells. Previously, we have shown that many breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-HER-2 antibodies). Our current work utilizes biochemical and genetic approaches to identify mechanisms that regulate the induction of death by TRAIL ligand in breast and ovarian cancer cells. Recently, we have shown that TRAIL selectively kills triple-negative breast cancer cells that have mesenchymal features. Ongoing work is exploring this observation further using clinically relevant TRAIL agonists alone and in combination with other targeted agents. We are also investigating the molecular basis for this selectivity by using a functional genomic approach. Triple negative breast cancer, defined by the absence of hormone receptors and the absence of HER-2 amplification has a poor prognosis and at present can only be treated with chemotherapy. These data suggest that TRAIL agonists may have therapeutic efficacy in a subset of triple negative breast cancer patients.